Several studies of abacavir (Ziagen) were presented at the recent International Conference on AIDS in Durban. Most of the results are preliminary and are based only on interim analysis, but they do extend our knowledge of the use of the drug. They suggest that short-term use of a three-drug combination containing abacavir may be as effective as a three-drug combination including a protease inhibitor. If these results hold up in longer term use, it will suggest there are many reasonable options for achieving good success with an initial three drug regimen and perhaps it doesn't matter whether the combination employs a protease inhibitor, a non-nucleoside drug or three drugs from the nucleoside class.

Encouraging results were also presented from a study using lopinavir
(Kaletra) among people who have previously taken multiple protease inhibitor-containing regimens.

Abacavir Studies

One abacavir study involved 195 people who had not previously taken anti-HIV therapies and who had an average viral load of around 16,000 copies HIV RNA and CD4+ cell counts of about 400. Participants received
either Combivir (AZT+3TC) + nelfinavir (Viracept) or Combivir + abacavir. The dose of nelfinavir used in this study was 750mg three times a day. The preliminary results after 24 weeks are shown in Table 1.

Table 1: Study of 195 People After 24 Weeks

Drug Combination

HIV RNA <50 copies

HIV RNA <400 copies

CD4+ cell increase

CBV+ABV

67%

72%

91

CBV+NFV

66%

71%

65

ABV = Abacavir; CBV = Combivir; NFV = Nelfinavir

In short, there was no significant difference. Moreover, the results
were the same for people who started with either a high or low viral load. A previous study had shown that people who had over 100,000 copies HIV RNA at study entry did not respond as well to abacavir compared to those with lower viral loads.

A similar study involved 342 people who had not previously taken anti-HIV therapies and who had an average viral load of around 63,000 copies HIV RNA and CD4+ cell counts averaging 300. In this study, participants received Combivir + abacavir or Combivir + indinavir (Crixivan). The preliminary results after 24 weeks are shown in Table 2.

Table 2: Study of 342 People After 24 Weeks

Drug Combination

HIV RNA<50 copies

HIV RNA<400 copies

CD4+ cell increase

Discontinued Drug

<1 missed dose/week

CBV+ABV

63%

78%

114

8%

74%

CBV+IDV

50%

57%

107

12%

45%

ABV = Abacavir; CBV = Combivir; IDV = Indinavir

At the very least, there was no significant difference and even some evidence of a small trend in favor of the abacavir regimen. This does not prove, however, that the abacavir regimen was more potent than the indinavir regimen. This study collected information on adherencethe degree to which participants took their drugs as ordered by the study. The data showed that perhaps more than any other factor, ease of use of the abacavir-containing regimen (two pills twice a day) resulted in substantially better adherence compared to the indinavir-containing regimen, which greatly influenced the outcome of this study.

Another study reported on results from using abacavir as part of a four-drug regimen. People received either a four-drug regimen of Combivir + abacavir + amprenavir (Agenerase) or a three-drug regimen of Combivir + nelfinavir. Combivir is a combination of AZT and 3TC in a single pill and thus counts as two drugs. The study followed 302 people who had not previously taken anti-HIV therapies and had an average viral load of about 40,000 copies HIV RNA and CD4+ cell counts of about 350. The final results, in terms of the percentage of people who sustained viral load under the limit of detection after 64 weeks are shown in Table 3.

Table 3: Study of 302 People After 64 Weeks

Drug Combination

HIV RNA <400 copies

HIV RNA <40 copies

CBV+ABV+APV

41%

37%

CBV+NFV

44%

34%

ABV = Abacavir; APV = Amprenavir; CBV = Combivir; NFV = Nelfinavir

The most disappointing aspect of this study is the poor response rate in both groups. There may be a number of contributing factors to this. Some of this is due to the use of a strict intent to treat analysis, which presents a worst-case analysis of the results. People receiving the four-drug combination experienced a lot of side effects, especially nausea, vomiting, diarrhea and rash, leading many people to drop out and perhaps others to deliberately miss doses of the drugs. Another factor may have been the difficulty many people report when using amprenavir. Use of the drug requires taking many large and difficult-to-swallow pills. Poor adherence may have eliminated any possible advantage from the use of the fourth drug. Additionally, as Project Inform reported in PI Perspective #29, there are increasing concerns regarding the long-term potency of nelfinavir.

Another concern is that ten percent of people on the four-drug regimen developed signs of a known problem with abacavir called hypersensitivity. Signs and symptoms of hypersensitivity usually include fever, rash, fatigue, nausea, vomiting, diarrhea, abdominal pain or respiratory symptoms such as pharyngitis (inflammation of the pharynx), difficulty in breathing or cough. People who develop or are thought to have these hypersensitivity symptoms should stop taking abacavir and should not try restarting the drug. However, there have been recent reports of people developing hypersensitivity reactions within hours to weeks of restarting abacavir even though they had no signs of hypersensitivity to the drug previously. People considering restarting abacavir should be particularly mindful of these symptoms and abacavir should be stopped if any of these hypersensitivity symptoms develop.

Kaletra (formerly ABT-378 or lopinavir)

Encouraging results were recently presented from a small study using lopinavir (Kaletra) in people who have been on multiple protease inhibitor regimens but have not previously received a non-nucleoside reverse transcriptase inhibitor (NNRTI). Lopinavir is a new protease inhibitor that is co-formulated with a low dose of ritonavir (Norvir). Each capsule contains 133mg of a protease inhibitor that was called ABT-378 and 33mg of ritonavir. Fifty-seven people with an average viral load of about 32,000 copies and average CD4+ cell count of 270 participated in this study. The majority had some degree of resistance to three or more of the currently approved protease inhibitors. All participants started out on three lopinavir capsules (twice daily) in combination with efavirenz (Sustiva) and any nucleoside analogue drugs (NARTIs) of their choice. After fourteen days, half of the volunteers continued on this regimen while the other half continued on efavirenz and NARTIs but had their lopinavir dose increased to four capsules. The results after 24 weeks are:

Table 4: Study of 270 People on Lopinavir After 24 weeks

Drug Combination

HIV RNA <400 copies

HIV RNA CD4+ cell increase

3 capsules LPV+EFV+NARTIs

69%

48

4 capsules LPV+EFV+NARTIs

82%

41

LPV = Lopinavir; EFV = Efavirenz

The results seen from this study among people who have been on multiple protease inhibitors are better than those seen from any previous studies. It is not possible to determine how much of the anti-HIV effect is due to lopinavir or efavirenz, since none of the participants had previously taken NNRTIs. However, at least one earlier study in a similar, highly drug-resistant population also started efavirenz with two other new drugs but had little success. One important finding from this study is that efavirenz significantly decreases lopinavir levels and the higher dose (four capsules) of lopinavir should be used when efavirenz is included in the drug combination. As a result of this finding all of the volunteers in the study are now receiving the higher lopinavir dose. Be sure to read earlier reports in PI Perspective to understand what is different about lopinavir and why it might work even in protease inhibitor resistant people, even though it is technically cross-resistant to some other such drugs.

The Food and Drug Administration is likely to approve lopinavir in the fall of 2000 and it should be available in pharmacies shortly thereafter. Because lopinavir has a small quantity of ritonavir in it, people who have had reactions to ritonavir should use care when taking lopinavir.

Commentary

The short-term results with abacavir are quite encouraging and seem consistent with earlier studies. But it remains to be seen whether the results will hold up in the long-term. What is abundantly clear is that the simpler dosing of an abacavir + Combivir combination results in better adherence, an important consideration in the `real world' setting. However, there is increasing concern over the risk for hypersensitivity to abacavir especially in light of the recent reports where people developed hypersensitivity reactions after restarting the drug even though they had no previous signs of hypersensitivity.

All of the studies with lopinavir have been very encouraging and the
drug is likely to benefit people who have not previously been on anti-HIV therapies as well as those who have been on extensive previous therapy. It is important that, if possible, lopinavir be used in combination with one or two new drugs in order to get the maximum benefit.

This article was provided by Project Inform. It is a part of the publication Project Inform Perspective.
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